Septic shock is the leading cause of death in intensive care units in the United States. Clinical studies have shown that most patients dying of septic shock die with a state of refractory vascular collapse, i.e., a persistently low systemic vascular resistance. Many laboratories across the United States are actively engaged in attempts to elucidate the nature of the circulating substances in sepsis that underlie this vascular collapse. We have developed an in vitro model of vascular function which utilizes sections of rat thoracic aorta. These sections are precontracted with catecholamines and then exposed to sera from septic patients, sera from experimentally septic animals, or chemically purified putative mediators of sepsis. The ensuing vascular relaxation can be quantified and used as an index of activity of these substances. Ongoing studies have established that (1) both human and canine septic sera possess potent vascular depressant effects, (2) many of the putative mediators of sepsis (including endotoxin, interleukin-1, and interleukin-2) do not have vascular depressant effects, (3) the mediator TNF (tumor necrosis factor) produces vascular depression in a dose-dependent fashion which relies in part on the presence of an intact endothelium, and (4) the vascular depressant activity in human septic sera is not dialyzable and is not attenuated with pretreatment with anti-TNF antisera. Continuing efforts are aimed at the isolation and characterization of sepsis-related vascular depressant substances, which have importance to both our understanding of the pathophysiology of sepsis and our ability to reverse the manifestations of sepsis with appropriate immunotherapeutic agents.